Riluzole in Spinal Cord Injury Study

Brief description of study

The aim of this study is to evaluate efficacy and safety of riluzole in the treatment of
patients with acute SCI. The primary objective is to evaluate the superiority of riluzole, at
a dose of 2 x 100 mg the first 24 hours followed by 2 x 50 mg for the following 13 days after
injury, as compared to placebo, in change between 180 days and baseline in motor outcomes as
measured by International Standards for Neurological Classification of Spinal Cord Injury
Examination (ISNCSCI) Motor Score, in patients with acute traumatic SCI, presenting to the
hospital less than 12 hours after injury. Secondary objectives are to evaluate the effects of
riluzole on overall neurologic recovery, sensory recovery, functional outcomes, quality of
life outcomes, health utilities, mortality, and adverse events. The working hypothesis is
that the riluzole treated subjects will experience superior motor, sensory, functional, and
quality of life outcomes as compared to those receiving placebo, with an acceptable safety
profile.

Detailed Study Description

At present there are over 1 million people living with Spinal Cord Injury (SCI) in North
America alone, with annual costs for the acute treatment and chronic care of these patients
totaling four billion dollars USD. The worldwide prevalence of SCI is unknown, with estimates
ranging up to 250 million individuals. The incidence of SCI in developed countries has been
estimated to be between 10 - 40 cases per million inhabitants. In spite of the immense impact
of SCI at a personal and societal level, an effective and safe pharmacologic treatment for
SCI, shown to improve neurological and functional outcomes at long-term follow-up, remains
absent.

The final degree of neurological tissue destruction that occurs after traumatic SCI is a
product of both primary and secondary injury mechanisms. The primary mechanical injury to the
cord initiates a subsequent signaling cascade of deleterious down-stream events, known
collectively as secondary injury mechanisms. These secondary injury mechanisms include
ischemia, interstitial and cellular ionic imbalance, free radical formation, glutamatergic
excitotoxicity, lipid peroxidation and generation of arachidonic acid metabolites. Although
little can be done from a therapeutic standpoint to correct damage sustained during the
primary injury, by mitigating the evolution of secondary injury events there is opportunity
to preserve remnant viable neurological tissue and improve neurologic outcomes. There is
convincing evidence from the preclinical realm that the pharmacologic agent riluzole
attenuates certain aspects of the secondary injury cascade leading to diminished neurological
tissue destruction in animal SCI models. Riluzole, a sodium channel blocking benzothiazole
anticonvulsant, specifically exerts its neuroprotective effect by helping to maintain
neuronal cellular ionic balance and by reducing the release of excitotoxic glutamate in the
post-SCI setting. Several preclinical studies in the rodent SCI model have associated
administration of riluzole with increased neural tissue preservation at the site of injury,
in addition to improved behavioral outcomes, in comparison to administration of placebo or
other sodium channel blocking drugs. In the clinical realm, while riluzole has not been
studied extensively in the context of SCI, it has been widely used in the treatment of
amyotrophic lateral sclerosis (ALS). A 2007 Cochrane review, summarizing the findings of 4
placebo-controlled randomized trials, concluded that at a dose of 100 mg daily, riluzole is
safe and improves median survival by 2-3 months in patients with ALS. In regards to adverse
events (AEs), riluzole was well tolerated, although treated patients were 2.6 times more
likely to experience a three-fold increase in serum alanine transaminase (ALT) as compared to
patients treated with placebo. However, this effect was found to be uniformly reversible with
cessation of riluzole therapy and was only reported after several months of medication
administration. Recently, the clinical safety and pharmacokinetic profile of riluzole have
been studied in a multi-center pilot study in the context of traumatic SCI. A total of 36
patients received an oral dose of riluzole 50 mg twice daily for 2 weeks, with treatment
initiated within 12 hours of injury for all patients. The 12 hour dosing window, as well as
the 2 week duration of therapy, was chosen to match the period of medication administration
to the known period of glutamatergic excitotoxicity after SCI (several minutes after injury
until 2 weeks after injury). With the final analysis currently undergoing peer review,
completion of this study has confirmed the acceptable safety profile of riluzole
administration previously documented in the ALS literature, and has established the
feasibility of conducting a large-scale efficacy trial investigating this therapy.

At present, there is no specific pharmacological therapy that is given uniformly to all
patients with traumatic SCI. As a result, a placebo-controlled comparison group is ethical
and justifiable.

The aim of the current trial is to evaluate efficacy and safety of riluzole in the treatment
of patients with acute SCI.

The primary objective of the current Phase II/III trial is to evaluate the superiority of
riluzole, at a dose of 2 x 100 mg the first 24 hours followed by 2 x 50 mg for the following
13 days after injury, as compared to placebo, in change between 180 days and baseline in
motor outcomes as measured by International Standards for Neurological Classification of
Spinal Cord Injury Examination (ISNCSCI) Motor Score, in patients with acute traumatic SCI,
presenting to the hospital less than 12 hours after injury.

Secondary objectives are to evaluate the effects of riluzole on overall neurologic recovery,
sensory recovery, functional outcomes, quality of life outcomes, health utilities, mortality,
and adverse events. The working hypothesis is that the riluzole treated subjects will
experience superior motor, sensory, functional, and quality of life outcomes as compared to
those receiving placebo, with an acceptable safety profile.